The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F-PY-PICA, 5F-PY-PINACA, and their analogs.

5F-PY-PICA and 5F-PY-PINACA are pyrrolidinyl 1-(5-fluoropentyl)ind (az)ole-3-carboxamides identified in 2015 as putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS). 5F-PY-PICA, 5F-PY-PINACA, and analogs featuring variation of the 1-alkyl substituent or contraction, expansion, or scission of the pyrrolidine ring were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS). In competitive binding experiments against HEK293 cells expressing human cannabinoid receptor type 1 (hCB ₁ ) or type 2 (hCB ₂ ), all analogs showed minimal affinity for CB ₁ (pK _i  < 5), although several demonstrated moderate CB ₂ binding (pK _i 5.45-6.99). In fluorescence-based membrane potential assays using AtT20-hCB ₁ or -hCB ₂ cells, none of the compounds (at 10 μM) produced an effect >50% of the classical cannabinoid agonist CP55,940 (at 1 μM) at hCB ₁ , although several showed slightly higher relative efficacy at hCB ₂ . Expansion of the pyrrolidine ring of 5F-PY-PICA to an azepane (8) conferred the greatest hCB ₂ affinity (pK _i 6.99) and activity (pEC ₅₀ 7.54, E _max 72%) within the series. Unlike other SCRA NPS evaluated in vivo using radio biotelemetry, 5F-PY-PICA and 5F-PY-PINACA did not produce cannabimimetic effects (hypothermia, bradycardia) in mice at doses up to 10 mg/kg.
(© 2019 John Wiley & Sons, Ltd.)